The long-term aim of this Project is to understand the anatomical and cellular abnormalities of the brain in Tourette's syndrome (TS). Many TS patients have histories of perinatal complications, and individuals with prenatal hypoxic/ischemic insults are at increased risk for chronic tic disorders and attention deficit hyperactivity disorder. We hypothesize that hypoxia and ischemia during the development of the basal ganglia are responsible in some cases for the impairments underlying TS. To test this hypothesis, animals that have undergone hypoxia and/or ischemia during the prenatal or the perinatal period will be analyzed to determine the specific cellular components that are affected. For normoxic and hypoxic animals, we will obtain volume and total number of phenotypically identified neurons and glia for various sub-regions of the basal ganglia. Similar analyses will be performed in postmortem human brains of TS and matched control subjects. These studies will determine whether there is a specific pattern of cell loss within the cortico-basal ganglia circuitry in hypoxia and in the brain of TS patients. We anticipate that neurons of the indirect pathway are the most susceptible to die from hypoxia and/or ischemia during the development of the basal ganglia. The proposed human morphometric studies are essential to identify whether similar cellular abnormalities also exist in the brain of TS subjects. Our study may give important clues as to whether hypoxia represents a risk factor for TS. The findings of this project will help the interpretation of in vivo morphometric abnormalities in TS and may guide future research and neurobiological testing on candidate vulnerability genes. Thus, our study may provide a mechanistic framework that would help interpret environmental risk factors, genetic variables, and the clinical phenotype of TS.